Glucokinase (GK) is one of four hexokinases that are found in mammals [Colowick, S. P., in The Enzymes, Vol. 9 (P. Boyer, ed.) Academic Press, New York, N.Y., pages 1-48, 1973]. The hexokinases catalyze the first step in the metabolism of glucose, i.e., the conversion of glucose to glucose-6-phosphate. Glucokinase has a limited cellular distribution, being found principally in pancreatic xcex2-cells and liver parenchymal cells. In addition, GK is a rate-controlling enzyme for glucose metabolism in these two cell types that are known to play critical roles in whole-body glucose homeostasis [Chipkin, S. R., Kelly, K. L., and Ruderman, N. B. in Joslin""s Diabetes (C. R. Khan and G. C. Wier, eds.), Lea and Febiger, Philadelphia, Pa., pages 97-115, 1994]. The concentration of glucose at which GK demonstrates half-maximal activity is approximately 8 mM. The other three hexokinases are saturated with glucose at much lower concentrations ( less than 1 mM). Therefore, the flux of glucose through the GK pathway rises as the concentration of glucose in the blood increases from fasting (5 mM) to postprandial (≈10-15 mM) levels following a carbohydrate-containing meal [Printz, R. G., Magnuson, M. A., and Granner, D. K. in Ann. Rev. Nutrition Vol. 13 (R. E. Olson, D. M. Bier, and D. B. McCormick, eds.), Annual Review, Inc., Palo Alto, Calif., pages 463-496, 1993]. These findings contributed over a decade ago to the hypothesis that GK functions as a glucose sensor in xcex2-cells and hepatocytes (Meglasson, M. D. and Matschinsky, F. M. Amer. J Physiol. 246, E1-E13, 1984). In recent years, studies in transgenic animals have confirmed that GK does indeed play a critical role in whole-body glucose homeostasis. Animals that do not express GK die within days of birth with severe diabetes while animals overexpressing GK have improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. et al., Cell 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al., FASEB J, 10, 1213-1218, 1996). An increase in glucose exposure is coupled through GK in xcex2-cells to increased insulin secretion and in hepatocytes to increased glycogen deposition and perhaps decreased glucose production.
The finding that type II maturity-onset diabetes of the young (MODY-2) is caused by loss of function mutations in the GK gene suggests that GK also functions as a glucose sensor in humans (Liang, Y., Kesavan, P., Wang, L. et al., Biochem. J 309, 167-173, 1995). Additional evidence supporting an important role for GK in the regulation of glucose metabolism in humans was provided by the identification of patients that express a mutant form of GK with increased enzymatic activity. These patients exhibit a fasting hypoglycemia associated with an inappropriately elevated level of plasma insulin (Glaser, B., Kesavan, P., Heyman, M. et al., New England J Med. 338, 226-230, 1998). While mutations of the GK gene are not found in the majority of patients with type II diabetes, compounds that activate GK and, thereby, increase the sensitivity of the GK sensor system will still be useful in the treatment of the hyperglycemia characteristic of all type II diabetes. Glucokinase activators will increase the flux of glucose metabolism in xcex2-cells and hepatocytes, which will be coupled to increased insulin secretion. Such agents would be useful for treating type II diabetes.
This invention provides a compound, comprising an amide of formulae Ia, Ib, IIa or IIb: 
wherein R1 is an alkyl having from 1 to 3 carbon atoms; R2 is hydrogen, halo, nitro, cyano, or perfluoro-methyl; R3 is a cycloalkyl having from 4 to 7 carbon atoms or 2-propyl; Z is xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94or xe2x80x94CHxe2x95x90CR4xe2x80x94CHxe2x95x90CHxe2x80x94, wherein R4 is hydrogen, halo, or an alkyl sulfone having from 1 to 3 carbon atoms; W is O, S or NH; and * denotes an asymmetric carbon atom; or a pharmaceutically acceptable salt thereof; or 
wherein R3 is a cycloalkyl having from 4 to 7 carbon atoms or 2-propyl; R5 is a halogen, preferably Cl or F; R6 is a halogen, preferably Cl or F; Z is xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94or xe2x80x94CHxe2x95x90CR4xe2x80x94CHxe2x95x90CHxe2x80x94, wherein R4 is hydrogen, halo, or an alkyl sulfone having from 1 to 3 carbon atoms; W is O, S or NH; and * denotes an asymmetric carbon atom; or a pharmaceutically acceptable salt thereof; or 
wherein R1 is an alkyl having from 1 to 3 carbon atoms; R2 is hydrogen, halo, nitro, cyano, or perfluoro-methyl; R3 is a cycloalkyl having from 4 to 7 carbon atoms or 2-propyl; each Y is independently CH or N; dotted lines collectively represent 0 or 2 additional double bonds in the heterocyclic ring structure; and * denotes an asymmetric carbon atom; or a pharmaceutically acceptable salt thereof; or 
wherein R3 is a cycloalkyl having from 4 to 7 carbon atoms or 2-propyl; R5 is a halogen, preferably Cl or F; R6 is a halogen, preferably Cl or F; each Y is independently CH or N; dotted lines collectively represent 0 or 2 additional double bonds in the heterocyclic ring structure; and * denotes an asymmetric carbon atom; or a pharmaceutically acceptable salt thereof.
The compounds of formulae Ia, Ib, IIa and IIb have been found to activate glucokinase in vitro. Glucokinase activators are useful for increasing insulin secretion in the treatment of type II diabetes.
This invention provides a compound, comprising an amide of the formulae Ia, Ib, IIa or IIb: 
wherein R1 is an alkyl having from 1 to 3 carbon atoms; R2 is hydrogen, halo, nitro, cyano, or perfluoro-methyl; R3 is a cycloalkyl having from 4 to 7 carbon atoms or 2-prpoyl; Z is xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94or xe2x80x94CHxe2x95x90CR4xe2x80x94CHxe2x95x90CHxe2x80x94, wherein R4 is hydrogen, halo, or an alkyl sulfone having from 1 to 3 carbon atoms; and W is O, S or NH; or a pharmaceutically acceptable salt thereof; or 
wherein R3 is a cycloalkyl having from 4 to 7 carbon atoms or 2-propyl; R5 is Cl or F; R6 is Cl or F; Z is xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94or xe2x80x94CHxe2x95x90CR4xe2x80x94CHxe2x95x90CHxe2x80x94,wherein R4 is hydrogen, halo, or an alkyl sulfone having from 1 to 3 carbon atoms; and W is O, S or NH; or a pharmaceutically acceptable salt thereof; or 
wherein R1 is an alkyl having from 1 to 3 carbon atoms; R2 is hydrogen, halo, nitro, cyano, or perfluoro-methyl; R3 is a cycloalkyl having from 4 to 7 carbon atoms or 2-propyl; each Y is independently CH or N; dotted lines collectively represent 0 or 2 additional double bonds in the heterocyclic ring structure; or a pharmaceutically acceptable salt thereof, or 
wherein R3 is a cycloalkyl having from 4 to 7 carbon atoms or 2-propyl; R5 is Cl or F; R6 is Cl or F; each Y is independently CH or N; and dotted lines collectively represent 0 or 2 additional double bonds in the heterocyclic ring structure; or a pharmaceutically acceptable salt thereof.
In formulae Ia, Ib, IIa and IIb, * indicates an asymmetric carbon. A compound of formulae Ia, Ib, IIa or IIb may be present either as a racemate or in the xe2x80x9cRxe2x80x9d configuration at the asymmetric carbon shown. Compounds which are isolated xe2x80x9cRxe2x80x9d enantiomers are preferred.
In further preferred embodiments of formulae Ia, Ib, IIa and IIb, R3 is a cyclopentyl group.
In formulae IIa and IIb, the dotted lines collectively represent zero or two, preferably two additional double bonds in the heterocyclic ring. As an example, in 3-cyclopentyl-2-(3, 4-dichloro-phenyl)-N-quinolin-2-yl-propionamide, there are two additional double bonds in the heterocyclic ring.
In certain preferred amides of formulae Ia and IIa, R1 is CH3 and R2 is H. Examples of such amides are N-benzothiazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide and 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-quinolin-2-yl-propionamide.
In further preferred amides of formulae Ia and IIa, R1 is SO2CH3 and R2 is halo. Examples of such amides are N-benzooxazol-2-yl-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide; 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-quinolin-2-yl-propionamide; N-(1H-benzoimidazol-2-yl)-2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide; and 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-quinolin-2-yl-propionamide.
In yet further preferred amides of formulae Ia and IIa, R1 is CH3 and R2 is CN. Examples of such amides are N-benzothiazol-2-yl-2-(3-cyano-4methanesulfonyl-phenyl)-3-cyclopentyl-propionamide; N-benzooxazol-2-yl-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide; N-(1H-benzoimidazol-2-yl)-2-(3-cyano-4-methanesulfonyl-phenyl-)3-cyclopentyl-propionamide; and 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-quinolin-2-yl-propionamide.
In still other preferred amides of formulae Ia and IIa, R1 is CH3 and R2 is CF3. Examples of such amides are 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-quinolin-2-yl-propionamide; N-benzothiazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionamide; N-(1H-benzoimidazol-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3trifluoromethyl-phenyl)-propionamide; and N-benzooxazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionamide.
In still further amides of formulae Ia and IIa, R1 is CH3, and R2 is NO2. Examples of such amides are N-benzothiazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide; N-benzooxazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide; N-(1H-benzoimidazol-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide; and 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-quinolin-2-yl-propionamide.
In certain amides of formulae Ia and Ib, W is O.Examples of such amides include N-benzooxazol-2-yl-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide; and N-benzooxazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide.
In certain other amides of formulae Ia and Ib, W is S. Examples of such amides include N-benzothiazol-2-yl-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide; N-benzothiazol-2-yl-2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide; and N-benzothiazol-2-yl-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide.
In still other amides of formulae Ia and Ib, W is NH. Examples of such amides include N-(1H-benzoimidazol-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide; and N-(1H-benzoimidazol-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide.
In yet other amides of formulae Ia and Ib, Z is xe2x80x94CHxe2x95x90CR4xe2x80x94CHxe2x95x90CHxe2x80x94 and R4 is halo, methyl sulfone or ethyl sulfone. Examples of such amides include 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(6-fluoro-benzothiazol-2-yl)-propionamide; and 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(6-methanesulfonyl-benzothiazol-2-yl)-propionamide.
In certain preferred amides of formulae Ib and IIb, both R5 and R6 are Cl or both R5 and R6 are F. Most preferably, both R5 and R6 are Cl.
In certain amides of formulae IIa and IIb, both Y are CH. Examples of such amides include 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-quinolin-2-yl-propionamide; 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-quinolin-2-yl-propionamide; 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-quinolin-2-yl-propionamide; 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-quinolin-2-yl-propionamide; 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-quinolin-2-yl-propionamide; 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-quinolin-2-yl-propionamide; 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-quinolin-2-yl-propionamide; and 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-quinolin-2-yl-propionamide.
In certain other amides of formulae IIa and IIb, at least one Y is N.
In still other amides of formulae IIa and IIb, the dotted lines collectively represent two additional double bonds. Examples of such amides include 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-quinolin-2-yl-propionamide; 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-quinolin-2-yl-propionamide; 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-quinolin-2-yl-propionamide; 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-quinolin-2-yl-propionamide; 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-quinolin-2-yl-propionamide; 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-quinolin-2-yl-propionamide; 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-quinolin-2-yl-propionamide; and 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-quinolin-2-yl-propionamide.
In yet other amides of formulae Ia and IIb, the dotted lines collectively represent zero additional double bonds.
As used herein, the term xe2x80x9chalogenxe2x80x9d and the term xe2x80x9chaloxe2x80x9d, unless otherwise stated, designate all four halogens, i.e. fluorine, chlorine, bromine and iodine. A preferred halogen is chlorine.
As used throughout this application, the term xe2x80x9clower alkylxe2x80x9d includes both straight chain and branched chain alkyl groups having from 1 to 8 carbon atoms, preferably from 1 to 3 carbon atoms, such as methyl, ethyl, propyl, isopropyl, preferably methyl.
As used herein the term xe2x80x9carylxe2x80x9d signifies aryl mononuclear aromatic hydrocarbon groups such as phenyl, tolyl, etc. which can be unsubstituted or substituted in one or more positions with halogen, nitro, lower alkyl, or lower alkoxy substituents and polynuclear aryl groups, such as naphthyl, anthryl, and phenanthryl, which can be unsubstituted or substituted with one or more of the aforementioned groups. Preferred aryl groups are the substituted and unsubstituted mononuclear aryl groups, particularly phenyl.
As used herein, the term xe2x80x9clower alkoxyxe2x80x9d includes both straight chain and branched chain alkoxy groups having from 1 to 7 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, preferably methoxy and ethoxy.
As used herein, the term xe2x80x9clower alkanoic acidxe2x80x9d denotes lower alkanoic acids containing from 2 to 7 carbon atoms such as propionic acid, acetic acid and the like.
The term xe2x80x9caroylxe2x80x9d denotes aroic acids wherein aryl is as defined hereinbefore, with the hydrogen group of the COOH moiety removed. Among the preferred aroyl groups is benzoyl.
As used herein, xe2x80x9clower alkyl thioxe2x80x9d means a lower alkyl group as defined above where a thio group is bound to the rest of the molecule.
As used herein, xe2x80x9clower alkyl sulfonylxe2x80x9d means a lower alkyl group as defined above where a sulfonyl group is bound to the rest of the molecule.
As used herein, xe2x80x9ccycloalkylxe2x80x9d means a saturated hydrocarbon ring having from 3 to 10 carbon atoms, preferably from 3 to 7 carbon atoms. A preferred cycloalkyl is cyclopentyl.
As used herein, the term xe2x80x9clower alkoxyxe2x80x9d includes both straight chain and branched chain alkoxy groups having from 1 to 7 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, preferably methoxy and ethoxy.
During the course of the reaction the various functional groups such as the free carboxylic acid or hydroxy groups will be protected via conventional hydrolyzable ester or ether protecting groups. As used herein the term xe2x80x9chydrolyzable ester or ether protecting groupsxe2x80x9d designates any ester or ether conventionally used for protecting carboxylic acids or alcohols which can be hydrolyzed to yield the respective hydroxyl or carboxyl group. Exemplary ester groups useful for those purposes are those in which the acyl moieties are derived from a lower alkanoic, aryl lower alkanoic, or lower alkane dicarboxyclic acid. Among the activated acids which can be utilized to form such groups are acid anhydrides, acid halides, preferably acid chlorides or acid bromides derived from aryl or lower alkanoic acids. Example of anhydrides are anhydrides derived from monocarboxylic acid such as acetic anhydride, benzoic acid anhydride, and lower alkane dicarboxcyclic acid anhydrides, e.g. succinic anhydride as well as chloro formates e.g. trichloro and ethylchloro formate being preferred. A suitable ether protecting group for alcohols are, for example, the tetrahydropyranyl ethers such as 4-methoxy-5,6-dihydroxy-2H-pyranyl ethers. Others are aroylmethylethers such as benzyl, benzhydryl or trityl ethers or xcex1-lower alkoxy lower alkyl ethers, for example, methoxymethyl or allylic ethers or alkyl silylethers such as trimethylsilylether.
The term xe2x80x9camino protecting groupxe2x80x9d designates any conventional amino protecting group which can be cleaved to yield the free amino group. The preferred protecting groups are the conventional amino protecting groups utilized in peptide synthesis. Especially preferred are those amino protecting groups which are cleavable under mildly acidic conditions from about pH 2.0 to 3. Particularly preferred amino protecting groups are t-butylcarbamate (BOC), benzylcarbamate (CBZ), and 9-fluorenylmethylcarbamate (FMOC).
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d as used herein include any salt with both inorganic or organic pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, para-toluene sulfonic acid and the like. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d also includes any pharmaceutically acceptable base salt such as amine salts, trialkyl amine salts and the like. Such salts can be formed quite readily by those skilled in the art using standard techniques.
The compounds of formulae Ia, Ib, IIa and IIb can be prepared starting from the compound of formula V by the following Reaction Scheme: 
wherein R11 is Cl, F or an alkyl sulfone of 1 to 3 carbon atoms, and R12 is Cl or F when R11 is Cl or F and R12 is hydrogen, halo, nitro, cyano, or perfluoro-methyl when R11 is an alkyl sulfone; R3, W, and Y are as above, the dotted lines represent 0 or 2 additional double bonds in the heterocyclic ring, R14 is hydrogen when the dotted lines represent 0 additional double bonds, and R14 is hydrogen, halo, or an alkyl sulfone having from 1 to 3 carbon atoms when the dotted lines represent 2 additional double bonds, R15 is a hydrolyzable ester group and X is a halogen atom, preferably Br or I.
The carboxylic acids of formula V are known wherein R12 is hydrogen and R11 is mercapto (4-mercaptophenylacetic acid), methylthio (4-methylthiophenylacetic acid), or methylsulfonyl (4-methylsulfonylphenylacetic acid). The carboxylic acids of formula V wherein both of R11 and R12 are chloro or fluoro (3,4-dichlorophenylacetic acid and 3,4-difluorophenyl acetic acid, respectively) are known. The carboxylic acid of formula V wherein R11 is fluoro and R12 is chloro is also known (3-chloro-4-fluorophenylacetic acid). If necessary for further chemical modification to produce the desired substitutions at R11 and R 12, the carboxylic acids can be converted to the corresponding esters of lower alkyl alcohols using any conventional esterification methods.
All the reactions hereto forward are to be carried out on the lower alkyl esters of the carboxylic acids of formulae VI or VIII or may be carried out on the carboxylic acids of formulae V or IX themselves.
If it is desired to produce the compound of formula V wherein R11 is chloro and R12 is fluoro, the commercially available 4-chloro-3-fluorobenzoic acid may be used as starting material. In this reaction sequence, the 4-chloro-3-fluorobenzoic acid is first converted to the corresponding acyl chloride. Any conventioanl method of converting a carboxylic acid to an acyl chloride may be utilized to effect this conversion. This acyl chloride is then converted to the corresponding 4-chloro-3-fluorophenylacetic acid via the Arndt-Eistert synthesis of converting an acyl halide to a carboxylic acid with one additional carbon (see for example, Skeean, R. W.; Goel, O. P. Synthesis 1990, 628).
If it is desired to produce compounds of formula V where R12 is hydrogen and R11 is lower alkyl sulfonyl, the known 4-mercaptophenylacetic acid may be used as a starting material. The compound of formula V where R12 is hydrogen and R11 is mercapto may be alkylated by conventional methods (for example, with an alkyl halide) to the corresponding lower alkyl thio compounds of formula V. The lower alkyl thio compounds can then be converted to the corresponding lower alkyl sulfonyl compounds of formula V by oxidation. Any conventional method of oxidizing an alkyl thio substituent to the corresponding sulfone group can be utilized to effect this conversion.
On the other hand, if it is desired to produce the compounds of formula V where R12 is trifluoromethyl and R11 is lower alkyl sulfonyl, the known 4-fluoro-3-(trifluoromethyl)phenyl acetic acid can be used as a starting material. In this reaction, any conventional method of nucleophilic displacement of an aromatic fluorine group with a lower alkyl thiol can be utilized to effect this conversion (see for example, Boswell, G. E.; Licause, J. F. J. Org. Chem. 1995, 6592; Sheikh, Y. M. et al. J. Org. Chem. 1982, 4341; Brown, F. C. et al. J. Org. Chem. 1961, 4707). Once the compounds of formula V where R12 is trifluoromethyl and R11 is lower alkyl thio are available, they can be converted to the corresponding compounds of formula V where R12 is trifluoromethyl and R11 is lower alkyl sulfonyl using conventional oxidation procedures.
If it is desired to produce the compounds of formula V where R12 is bromo and R11 is lower alkyl sulfonyl, the compounds wherein R12 is hydrogen and R11 is lower alkyl thio, compounds produced as described above, can be used as starting materials. The phenyl acetic acid derivatives of formula V wherein R12 is hydrogen and R11 is lower alkyl thio can be brominated. Any conventional method of aromatic bromination can be utilized to effect this conversion (see for example, Wrobel, J. et al. J. Med. Chem. 1989, 2493). Once the compounds of formula V where R12 is bromo and R11 is lower alkyl thio are available, they can be converted to the corresponding compounds of formula V where R12 is bromo and R11 is lower alkyl sulfonyl by oxidation. Any conventional method of oxidizing an alkyl thio substituent to the corresponding sulfone group can be utilized to effect this conversion.
On the other hand, if it is desired to produce the compounds of formulae V or VI where R12 is nitro and R11 is lower alkyl sulfonyl, the known 4-chloro-3-nitrophenyl acetamide can be used as starting material. In this reaction sequence, any conventional method of converting a primary carboxamide to a carboxylic acid or carboxylic ester can be used to effect this conversion (see for example, Greenlee, W. J.; Thorsett, E. D. J Org. Chem., 1981, 5351). These compounds can then be converted to the compounds of formulae V or VI where R12 is nitro and R11 is lower alkyl thio. Any conventional method of nucleophilic displacement of an aromatic chlorine group with a lower alkyl thiol can be utilized to effect this conversion (see for example, Testaferri, L. et al. Synthesis 1983, 751). Once the compounds of formula V or VI where R12 is nitro and R11 is lower alkyl thio are available, they can be converted to the corresponding compounds of formula V or VI where R12 is nitro and R11 is lower alkyl sulfonyl by oxidation. Any conventional method of oxidizing an alkyl thio substituent to the corresponding sulfone group can be utilized to effect this conversion. On the other hand, if it is desired to directly produce the compounds of formulae V or VI where R12 is nitro and R11 is lower alkyl sulfonyl from the compounds of formulae V or VI where R12 is nitro and R11 is chloro, any conventional method of nucleophilic displacement of an aromatic chlorine group with a lower alkane sulfinate (such as sodium methane sulfinate) can be utilized to effect this conversion (see for example, Ulman, A.; Urankar, E. J Org. Chem., 1989, 4691).
If it is desired to produce compounds of formula V where R12 is chloro and R11 is lower alkyl sulfonyl, the known 2-chlorothiophenol can be used as starting material. In this reaction sequence, the mercapto group may be alkylated by conventional methods (for example, with a lower alkyl halide) to the corresponding 2-chloro-1-lower alkyl thio benzenes. These compounds can then be converted to the corresponding 3-chloro-4-(lower alkyl thio)-phenyl acetic acids. First, the 2-chloro-1-lower alkyl thio benzenes are acylated with a (lower alkyl)oxalyl chloride (such as methyloxalyl chloride or ethyloxalyl chloride) via a Friedel-Crafts acylation to produce the beta-keto carboxylic ester in the position para to the lower alkyl thio functional group. The beta-keto carboxylic ester is next hydrolyzed by any conventional method to convert a beta-keto carboxylic ester to a beta-keto carboxylic acid. Wolff-Kisner reduction of the resulting beta-keto carboxylic acid will produce the compounds of formula V where R12 is chloro and R11 is lower alkyl thio (see for example, Levine, S. D. J. Med. Chem. 1972, 1029 for a similar reaction sequence). The lower alkyl thio compounds can then be converted to the corresponding lower alkyl sulfonyl compounds of formula V by oxidation. Any conventional method of oxidizing an alkyl thio substituent to the corresponding sulfone group can be utilized to effect this conversion.
On the other hand, if it is desired to produce the compounds of formula V where R12 is cyano and R11 is lower alkyl sulfonyl, these compounds can be prepared as described hereinbefore from compounds where R12 is bromo and R11 is lower alkyl sulfonyl. Any conventional method of nucleophilic displacement of an aromatic bromine group with a cyano group transferring agent [such as copper(I) cyanide] can be utilized to effect this conversion. This conversion can take place either before or after the compound of formula V is converted to the compounds of formulae I and II.
If it is desired to produce the compounds of formula V where R12 is fluoro and R11 is lower alkyl sulfonyl, these compounds can be prepared as described hereinbefore from compounds where R12 is nitro and R11 is lower alkyl sulfonyl. The aromatic nitro substituent is first converted to the aromatic amino group. Any conventional method of reducing a nitro group to an amine can be utilized to effect this conversion. The amino group can then be converted to the fluorine group to produce the compounds of formula V where R12 is fluoro and R11 is lower alkyl sulfonyl. Any conventional method of converting an aromatic amino group to an aromatic fluorine can be utilized to effect this conversion (see for example, Milner, D. J. Synthetic Commun. 1992, 73; Fukuhara, T. et al. J. Fluorine Chem. 1991, 299). This conversion can take place either before or after the compound of formula V is converted to the compound of formulae I or II.
For the alkylation reaction using the alkyl halide of formula VII, the carboxylic acids of formula V can be directly alkylated or first converted to the corresponding esters of lower alkyl alcohols of formula VI using any conventional esterification methods and then alkylated. In the alkylation step of the Reaction Scheme, the alkyl halide of formula VII is reacted with the compound of formula V to produce the compound of formula IX or reacted with the compound of formula VI to produce the compound of formula VIII. The compounds of formulae V and VI represent an organic acid and an organic acid derivative having an alpha carbon atom, and the compound of formula VII is an alkyl halide so that alkylation occurs at the alpha carbon atom of this carboxylic acid. This reaction is carried out by any conventional means of alkylation of the alpha carbon atom of a carboxylic acid or a lower alkyl ester of a carboxylic acid. Generally, in these alkylation reactions an alkyl halide is reacted with the dianion of the acetic acid or the anion generated from an acetic acid ester. The anion can be generated by using a strong organic base such as lithium diisopropylamide and n-butyl lithium as well as other organic lithium bases. In carrying out this reaction, low boiling ether solvents are utilized such as tetrahydrofuran at low temperatures from xe2x88x9280xc2x0 C. to about xe2x88x9210xc2x0 C. being preferred. However any temperature from xe2x88x9280xc2x0 C. to room temperature can be used.
The compound of formula VIII can be converted to the compound of formula IX by any conventional procedure to convert a carboxylic acid ester to an acid. The compound of formula IX is condensed with the compounds of formulae X or XI via conventional peptide coupling to produce the compounds of formulae I or II, respectively. In carrying out this reaction, any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
The amine of formula X is a five-membered heteroaromatic ring fused with a aromatic ring which contains six ring members or fused with a saturated six-membered cycloalkyl ring. The five-membered heteroaromatic ring contains 2 heteroatoms selected from the group consisting of oxygen, sulfur, or nitrogen and is connected by a ring carbon to the amine of the amide group shown in formula I. This five-membered heteroaromatic ring contains a first nitrogen heteroatom adjacent to the connecting ring carbon atom, and the other heteroatoms defined by W can be sulfur, oxygen or nitrogen. There are no heteroatoms on the fusion points. Such five-membered heteroaromatic fused rings defined by formula X include, for example, benzothiazole, benzoxazole, benzoimidazole, and tetrahydrobenzothiazole. These heteroaromatic rings are connected via a ring carbon atom to the amide group to form the amides of formula I. The ring carbon atom of the heteroaromatic ring which is connected via the amide linkage to form the compound of formula I cannot contain any substituent.
The amine of formula XI is a six-membered heteroaromatic ring fused with a aromatic ring which contains six ring members or fused with a saturated six-membered cycloalkyl ring. The six-membered heteroaromatic ring contains 1 to 3 nitrogen heteroatoms and is connected by a ring carbon to the amine of the amide group shown in formula II. This six-membered heteroaromatic ring contains a first nitrogen heteroatom adjacent to the connecting ring carbon atom, and if present, Y defines the location of the other nitrogen heteroatoms. There are no heteroatoms on the fusion points. Such six-membered heteroaromatic fused rings defined by formula XI include, for example, quinoline, quinazoline, quinoxaline, benzotriazine, and tetrahydroquinoline. These heteroaromatic rings are connected via a ring carbon atom to the amide group to form the amides of formula II. The ring carbon atom of the heteroaromatic ring which is connected via the amide linkage to form the compound of formula II cannot contain any substituent.
The required amino heteroaromatic compounds of formulae X and XI are commercially available or can be prepared from the reported literature.
The compound of formulae I and II has an asymmetric carbon atom through which the group xe2x80x94CH2R3 and the acid amide substituents are connected. In accordance with this invention, the preferred stereoconfiguration of this group is R.
If it is desired to produce the R or the S isomer of the compounds of formulae I and II, these compounds can be isolated as the desired isomer by any conventional chemical means. The preferred chemical mean is the use of pseudoephredrine as a chiral auxiliary for the asymmetric alkylation of the phenylacetic acids of formula V (see for example, Myers, A. G. et al. J Am. Chem. Soc. 1997, 6496). To form the desired R acids of formula IX, the compounds of formula V where R12 is lower alkyl thio and R11 is as described above are first converted to the pseudoephedrine amides using 1R,2R-(-)-pseudoephedrine as the desired enantiomer of pseudoephedrine. Any conventional method of converting a carboxylic acid to a carboxamide can be utilized to effect this conversion. The pseudoephedrine amides can undergo highly diastereoselective alkylations with alkyl halides to afford the xcex1-substituted amide products corresponding to formula IX. These highly diastereomerically enriched amides can be converted to the highly enantiomerically enriched R carboxylic acids of formula IX where R12 is lower alkyl thio and R11 is as described above by conventional acidic hydrolysis methods to convert a carboxamide to a carboxylic acid. These R carboxylic acids of formula IX where R12 is lower alkyl thio and R11 is as described above can be converted to the R isomers of formulae I and II where R12 is lower alkyl thio and R11 is as described above. In carrying out this reaction, any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion. Once the compounds of formulae I and II where R12 is lower alkyl thio and R11 is as described above are available, they can be converted to the corresponding R compounds of formulae I and II where R12 is lower alkyl sulfonyl and R11 is as described above by oxidation. Any conventional method of oxidizing an alkyl thio substituent to the corresponding sulfone group can be utilized to effect this conversion.
On the other hand, the R carboxylic acids of formula IX where R12 is lower alkyl thio and R11 is as described above can first be oxidized to the R compounds of formula IX where R12 is lower alkyl sulfonyl and R1 is as described above. Any conventional method of oxidizing an alkyl thio substituent to the corresponding sulfone group can be utilized to effect this conversion. These compounds can be then converted to the corresponding R compounds of formulae I and II where R12 is lower alkyl sulfonyl and R11 is as described above. In carrying out this reaction, any conventional method of condensing a primary amine with a carboxylic acid, without racemization, can be utilized to effect this conversion.
Another chemical means to produce the R or S isomer of the compounds of formulae I or II is to react the compound of formula IX with an optically active base. Any conventional optically active base can be utilized to carry out this resolution. Among the preferred optically active bases are the optically active amine bases such as alpha-methylbenzylamine, quinine, dehydroabietylamine and alpha-methylnaphthylamine. Any of the conventional techniques utilized in resolving organic acids with optically active organic amine bases can be utilized in carrying out this reaction. In the resolution step, the compound of formula IX is reacted with the optically active base in an inert organic solvent medium to produce salts of the optically active amine with both the R and S isomers of the compound of formula IX. In the formation of these salts, temperatures and pressure are not critical and the salt formation can take place at room temperature and atmospheric pressure. The R and S salts can be separated by any conventional method such as fractional crystallization. After crystallization, each of the salts can be converted to the respective compounds of formula IX in the R and S configuration by hydrolysis with an acid. Among the preferred acids are dilute aqueous acids , i.e., from about 0.001N to 2N aqueous acids, such as aqueous sulfuric or aqueous hydrochloric acid. The configuration of formula IX which is produced by this method of resolution is carried out throughout the entire reaction scheme to produce the desired R or S isomers of formulae I and II.
The resolution of racemates of the compounds of the formula IX can also be achieved via the formation of corresponding diastereomeric esters or amides. These diastereomeric esters or amides can be prepared by coupling the carboxylic acids of the formula IX with a chiral alcohol or a chiral amine. This reaction can be carried out using any conventional method of coupling a carboxylic acid with an alcohol or an amine. The corresponding diastereomers of compounds of the formula IX can then be separated using any conventional separation methods. The resulting pure diastereomeric esters or amides can then be hydrolyzed to yield the corresponding pure R or S isomers. The hydrolysis reaction can be carried out using conventional known methods to hydrolyze an ester or an amide without racemization. Finally, the separation of R and S isomers can also be achieved using an enzymatic ester hydrolysis of any lower alkyl esters corresponding to the compound of the formula IX (see for example, Ahmar, M.; Girard, C.; Bloch, R, Tetrahedron Lett, 1989, 7053), which results in the formation of corresponding chiral acid and chiral ester. The ester and the acid can be separated by any conventional method of separating an acid from an ester. The configuration of formula IX which is produced by this method of resolution is carried out throughout the entire reaction scheme to produce the desired R or S isomers of formulae I and II.
All of the compounds of formulae Ia, Ib, IIa and IIb, which include the compounds set forth in the Examples, activate glucokinase in vitro by the procedure of Example A. In this manner, they increase the flux of glucose metabolism which causes increased insulin secretion. Therefore, the compounds of formulae Ia, Ib, IIa and IIb are glucokinase activators useful for increasing insulin secretion.
The following compounds were tested and found to have excellent glucokinase activator in vivo activity when administered orally in accordance with the assay described in Example B:
N-Benzothiazol-2-yl-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide
N-(1H-benzoimidazol-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide
2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-quinolin-2-yl-propionamide
This invention will be better understood from the following examples, which are for purposes of illustration and are not intended to limit the invention defined in the claims that follow thereafter.